S-citalopram (escitalopram) is the active component of the product citalopram, which is a racemic mixture of the R- and S-enantiomers. The compound is a valuable antidepressant of the selective serotonin reuptake inhibitor (SSRI) type.
Both racemic citalopram and S-citalopram are marketed as antidepressant agents.
It has now surprisingly been found that a mixture of R- and S-citalopram containing more than than 50% of one or the enantiomers, i.e a non-racemic mixture, may be separated into a fraction of racemic citalopram and a fraction of S- or R-citalopram by precipitation of citalopram as the free base or as an acid addition salt thereof. The surplus of S-citalopram or R-citalopram may be isolated from the mother liquor of the precipitation.
This is an important and very useful process, in particular because it allows the preparation of racemic citalopram and S-citalopram from mixtures of R- and S-citalopram obtained from manufacturing processes which result in mixtures which do not meet the specifications of the marketing approval of neither racemic citalopram nor S-citalopram (in escitalopram, the amount of R-citalopram compared to S-citalopram should be less than 3%, preferably less).
S-citalopram may be prepared by separation of the R- and S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (the R- and S-diol) followed by ring closure of the S-diol with retention of configuration, as described in EP-B1-347 066.
Other processes for the preparation of S-citalopram including chromatographic separation of enantiomers are also available. It is for example possible to separate the corresponding bromo-derivative, 1-(4-Bromo-2-hydroxymethylphenyl)-4-dimethylamino-1-(4-fluorophenyl)butan-1-ol from the corresponding R-diol, followed by ring closure with retention of configuration and cyanation to form S-citalopram. Cyanation processes for citalopram are well known and have been described in U.S. Pat. No. 4,136,193, WO 00/11926 and WO 00/13648.
Depending on the specific process used and the conditions used, the enantiomeric purity of the S-citalopram product obtained may have to be improved.
Other processes for stereo-selective synthesis of S-citalopram may also result in mixtures of R-and S-citalopram which do not fulfil the specifications of the marketing approval of S-citalopram.
Thus, according to one aspect of the invention, the invention provides an easy way to improve the enantiomeric purity of S-citalopram obtained by such processes.
During the production of S-citalopram by chromatographic separation of R- and S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile followed by ring closure of S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile, the R-enantiomer of formula (I)
is formed as a by-product.
It has now been found that ring closure of a compound of formula I in an acidic environment provides a reaction mixture containing a surplus of S-citalopram compared to R-citalopram. In other words, ring closure in an acidic environment proceed with partial inversion of configuration.
Accordingly, the by-product of formula (I) may be used for the preparation of S-citalopram and racemic citalopram and the method for the production of S-citalopram has thereby become more rational and more economical in the utilisation of reagents and resources.